Ca2+/H+ exchange by acidic organelles regulates cell migration in vivo

Increasing evidence implicates Ca2+ in the control of cell migration. However, the underlying mechanisms are incompletely understood. Acidic Ca2+ stores are fast emerging as signaling centers. But how Ca2+ is taken up by these organelles in metazoans and the physiological relevance for migration is unclear. Here, we identify a vertebrate Ca2+/H+ exchanger (CAX) as part of a widespread family of homologues in animals. CAX is expressed in neural crest cells and required for their migration in vivo. It localizes to acidic organelles, tempers evoked Ca2+ signals, and regulates cell-matrix adhesion during migration. Our data provide new molecular insight into how Ca2+ is handled by acidic organelles and link this to migration, thereby underscoring the role of noncanonical Ca2+ stores in the control of Ca2+-dependent function.

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Supracellular organization confers directionality and mechanical potency to migrating pairs of cardiopharyngeal progenitor cells

10.1101/2021.02.09.430466 ◽

2021 ◽

Author(s):

Yelena Y. Bernadskaya ◽

Haicen Yue ◽

Calina Copos ◽

Lionel Christiaen ◽

Alex Mogilner

Keyword(s):

Cell Migration ◽

Cell Communication ◽

Biomechanical Properties ◽

Collective Cell Migration ◽

Cellular Potts Model ◽

Cellular Mechanics ◽

Cell Matrix ◽

Collective Movements ◽

Cell Matrix Adhesion

AbstractPhysiological and pathological morphogenetic events involve a wide array of collective movements, suggesting that these multicellular arrangements confer biochemical and biomechanical properties that contribute to tissue scale organization. The cardiopharyngeal progenitors of the tunicate Ciona provide the simplest possible model of collective cell migration. They form cohesive bilateral cell pairs, leader-trailer polarized along the migration path as they migrate between the ventral epidermis and trunk endoderm. Here, circumventing difficulties in quantifying cellular mechanics in live embryos, we use the Cellular Potts Model to computationally probe the distributions of forces consistent with the shapes and collective polarity of migrating cell pairs. Combining computational modeling, confocal microscopy, and molecular perturbations, we first determine that cardiopharyngeal progenitors display hallmarks of supracellular organization, with differential distributions of protrusive forces, cell-matrix adhesion, and myosin-based retraction forces along the leader-trailer axis. Combined 4D simulations and experimental observations suggest that cell-cell communication helps establish a hierarchy that contributes to aligning collective polarity with the direction of migration, as observed with three or more cells both in silico and in vivo. Our approach reveals emerging properties of the migrating collective. Specifically, cell pairs are more persistent, thus migrating over longer distances, and presumably with higher accuracy. Finally, simulations suggest that polarized cell pairs literally join forces to deform the trunk endoderm, as they migrate through the extracellular space. We thus propose that the polarized supracellular organization of cardiopharyngeal progenitors confers emergent physical properties that determine mechanical interactions with their environment during morphogenesis.

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MicroRNA-139-3p Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by Repressing ANXA2R

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504018x15178798885361 ◽

2018 ◽

Vol 26 (9) ◽

pp. 1391-1399 ◽

Cited By ~ 5

Author(s):

Zeng Cheng Zou ◽

Min Dai ◽

Zeng Yin Huang ◽

Yi Lu ◽

He Ping Xie ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Migration ◽

Cell Growth ◽

Mouse Model ◽

Migration And Invasion ◽

Tumor Growth And Metastasis ◽

Underlying Mechanisms ◽

Hcc Cells

The direct roles of miR-139-3p on hepatocellular carcinoma (HCC) cell growth and metastasis remain poorly understood. We attempted to demonstrate the regulatory role of miR-139-3p in HCC progression and its underlying mechanisms. Here we showed that miR-139-3p expression was significantly reduced in the HCC tissues compared to paratumor tissues. Exogenous overexpression of miR-139-3p inhibited the migration and invasion of HCC cells, whereas downregulation of miR-139-3p was able to induce HCC HepG2 and SNU-449 cell migration and invasion. In addition, miR-139-3p inhibited HCC growth and lung metastasis in an in vivo mouse model, which is mainly regulated by annexin A2 receptor (ANXA2R). Finally, we identified that the expression of miR-139-3p was inversely correlated with ANXA2R expression in human HCC tissue. All these results demonstrated that miR-139-3p inhibited the metastasis process in HCC by downregulating ANXA2R expression.

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The mechanosensitive channel Piezo1 cooperates with Semaphorin to control neural crest migration

Development ◽

10.1242/dev.200001 ◽

2021 ◽

Author(s):

Brenda Canales Coutiño ◽

Roberto Mayor

Keyword(s):

Cell Migration ◽

Neural Crest ◽

Embryonic Cell ◽

Extracellular Signals ◽

Rac1 Activity ◽

Cytoskeletal Dynamics ◽

Mechanosensitive Ion Channel ◽

Neural Crest Migration

Cells are permanently exposed to a multitude of different kind of signals; however how cells respond to simultaneous extracellular signals within a complex in vivo environment is poorly understood. Here, we studied the role of the mechanosensitive ion channel Piezo1 on the migration of the neural crest (NC), a multipotent embryonic cell population. We identify that Piezo1 is required for the migration of Xenopus cephalic NC. We show that loss of Piezo1 promotes focal adhesion turnover and cytoskeletal dynamics by controlling Rac1 activity, leading to increased speed of migration. Moreover, overactivation of Rac1, due to Piezo1 inhibition, counteracts cell migration inhibitory signals by Semaphorins 3A and 3F, generating aberrant neural crest invasion in vivo. Thus, we find that, for directional migration in vivo, neural crest cells require a tight regulation of Rac1, by Semaphorins and Piezo1. We reveal here that a balance between a myriad of signals through Rac1 dictates cell migration in vivo, a mechanism that is likely to be conserved in other cell migration processes.

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Podokinesis in endothelial cell migration: role of nitric oxide

AJP Cell Physiology ◽

10.1152/ajpcell.1998.274.1.c236 ◽

1998 ◽

Vol 274 (1) ◽

pp. C236-C244 ◽

Cited By ~ 123

Author(s):

Eisei Noiri ◽

Eugene Lee ◽

Jacqueline Testa ◽

James Quigley ◽

David Colflesh ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Cell Migration ◽

Endothelial Cell ◽

No Synthase ◽

Endothelial Cell Migration ◽

Guidance Cues ◽

Cell Matrix ◽

Cell Matrix Adhesion

Previously, we demonstrated the role of nitric oxide (NO) in transforming epithelial cells from a stationary to locomoting phenotype [E. Noiri, T. Peresleni, N. Srivastava, P. Weber, W. F. Bahou, N. Peunova, and M. S. Goligorsky. Am. J. Physiol. 270 ( Cell Physiol. 39): C794–C802, 1996] and its permissive function in endothelin-1-stimulated endothelial cell migration (E. Noiri, Y. Hu, W. F. Bahou, C. Keese, I. Giaever, and M. S. Goligorsky. J. Biol. Chem. 272: 1747–1753, 1997). In the present study, the role of functional NO synthase in executing the vascular endothelial growth factor (VEGF)-guided program of endothelial cell migration and angiogenesis was studied in two independent experimental settings. First, VEGF, shown to stimulate NO release from simian virus 40-immortalized microvascular endothelial cells, induced endothelial cell transwell migration, whereas N G-nitro-l-arginine methyl ester (l-NAME) or antisense oligonucleotides to endothelial NO synthase suppressed this effect of VEGF. Second, in a series of experiments on endothelial cell wound healing, the rate of VEGF-stimulated cell migration was significantly blunted by the inhibition of NO synthesis. To gain insight into the possible mode of NO action, we next addressed the possibility that NO modulates cell matrix adhesion by performing impedance analysis of endothelial cell monolayers subjected to NO. The data showed the presence of spontaneous fluctuations of the resistance in ostensibly stationary endothelial cells. Spontaneous oscillations were induced by NO, which also inhibited cell matrix adhesion. This process we propose to term “podokinesis” to emphasize a scalar form of micromotion that, in the presence of guidance cues, e.g., VEGF, is transformed to a vectorial movement. In conclusion, execution of the program for directional endothelial cell migration requires two coexisting messages: NO-induced podokinesis (scalar motion) and guidance cues, e.g., VEGF, which imparts a vectorial component to the movement. Such a requirement for the dual signaling may explain a mismatch in the demand and supply with newly formed vessels in different pathological states accompanied by the inhibition of NO synthase.

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Cell matrix adhesion in cell migration

Essays in Biochemistry ◽

10.1042/ebc20190012 ◽

2019 ◽

Vol 63 (5) ◽

pp. 535-551 ◽

Cited By ~ 13

Author(s):

James R.W. Conway ◽

Guillaume Jacquemet

Keyword(s):

Cell Migration ◽

Immune Surveillance ◽

Tissue Homeostasis ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Cell Matrix ◽

Signalling Cascades ◽

Cell Matrix Adhesion ◽

Extracellular Environment

Abstract The ability of cells to migrate is a fundamental physiological process involved in embryonic development, tissue homeostasis, immune surveillance and wound healing. In order for cells to migrate, they must interact with their environment using adhesion receptors, such as integrins, and form specialized adhesion complexes that mediate responses to different extracellular cues. In this review, we discuss the role of integrin adhesion complexes (IACs) in cell migration, highlighting the layers of regulation that are involved, including intracellular signalling cascades, mechanosensing and reciprocal feedback to the extracellular environment. We also discuss the role of IACs in extracellular matrix remodeling and how they impact upon cell migration.

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Plasminogen Activation In Vivo upon Intravenous Infusion of DDAVP

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648390 ◽

1992 ◽

Vol 67 (01) ◽

pp. 111-116 ◽

Cited By ~ 64

Author(s):

Marcel Levi ◽

Jan Paul de Boer ◽

Dorina Roem ◽

Jan Wouter ten Cate ◽

C Erik Hack

Keyword(s):

Monoclonal Antibodies ◽

Plasminogen Activator ◽

Plasma Levels ◽

Fold Increase ◽

Fibrinolytic System ◽

Plasminogen Activation ◽

Plasminogen Activator Activity ◽

Insight Into

SummaryInfusion of desamino-d-arginine vasopressin (DDAVP) results in an increase in plasma plasminogen activator activity. Whether this increase results in the generation of plasmin in vivo has never been established.A novel sensitive radioimmunoassay (RIA) for the measurement of the complex between plasmin and its main inhibitor α2 antiplasmin (PAP complex) was developed using monoclonal antibodies preferentially reacting with complexed and inactivated α2-antiplasmin and monoclonal antibodies against plasmin. The assay was validated in healthy volunteers and in patients with an activated fibrinolytic system.Infusion of DDAVP in a randomized placebo controlled crossover study resulted in all volunteers in a 6.6-fold increase in PAP complex, which was maximal between 15 and 30 min after the start of the infusion. Hereafter, plasma levels of PAP complex decreased with an apparent half-life of disappearance of about 120 min. Infusion of DDAVP did not induce generation of thrombin, as measured by plasma levels of prothrombin fragment F1+2 and thrombin-antithrombin III (TAT) complex.We conclude that the increase in plasminogen activator activity upon the infusion of DDAVP results in the in vivo generation of plasmin, in the absence of coagulation activation. Studying the DDAVP induced increase in PAP complex of patients with thromboembolic disease and a defective plasminogen activator response upon DDAVP may provide more insight into the role of the fibrinolytic system in the pathogenesis of thrombosis.

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Role of interleukins in the pathogenesis of pulmonary fibrosis

Cell Death Discovery ◽

10.1038/s41420-021-00437-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yi Xin She ◽

Qing Yang Yu ◽

Xiao Xiao Tang

Keyword(s):

Pulmonary Fibrosis ◽

Therapeutic Strategy ◽

Future Directions ◽

Regulation Mechanisms ◽

Underlying Mechanisms ◽

Multiple Cells ◽

The Relationship

AbstractInterleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. In this article, we reviewed the relationship between interleukins and pulmonary fibrosis from the clinical, animal, as well as cellular levels, and discussed the underlying mechanisms in vivo and in vitro. Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. Intervening interleukins combined with other existing therapy or targeting interleukins affecting multiple cells/with different functions at the same time may be one of the future directions. Furthermore, the intervention time is critical as some interleukins play different roles at different stages. Further elucidation on these aspects would provide new perspectives on both the pathogenesis mechanism, as well as the therapeutic strategy and drug development.

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Oxidized LDLs as Signaling Molecules

Antioxidants ◽

10.3390/antiox10081184 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1184

Author(s):

Jean-Marc Zingg ◽

Adelina Vlad ◽

Roberta Ricciarelli

Keyword(s):

Free Radicals ◽

Cellular Response ◽

Vascular System ◽

Signaling Molecules ◽

Scavenger Receptors ◽

Physiological Relevance ◽

Reactive Radicals ◽

Accumulation Of Lipids

Levels of oxidized low-density lipoproteins (oxLDLs) are usually low in vivo but can increase whenever the balance between formation and scavenging of free radicals is impaired. Under normal conditions, uptake and degradation represent the physiological cellular response to oxLDL exposure. The uptake of oxLDLs is mediated by cell surface scavenger receptors that may also act as signaling molecules. Under conditions of atherosclerosis, monocytes/macrophages and vascular smooth muscle cells highly exposed to oxLDLs tend to convert to foam cells due to the intracellular accumulation of lipids. Moreover, the atherogenic process is accelerated by the increased expression of the scavenger receptors CD36, SR-BI, LOX-1, and SRA in response to high levels of oxLDL and oxidized lipids. In some respects, the effects of oxLDLs, involving cell proliferation, inflammation, apoptosis, adhesion, migration, senescence, and gene expression, can be seen as an adaptive response to the rise of free radicals in the vascular system. Unlike highly reactive radicals, circulating oxLDLs may signal to cells at more distant sites and possibly trigger a systemic antioxidant defense, thus elevating the role of oxLDLs to that of signaling molecules with physiological relevance.

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Gastric Hyperplasia and Increased Proliferative Responses of Lymphocytes in Mice Lacking the COOH-terminal Ankyrin Domain of NF-κB2

Journal of Experimental Medicine ◽

10.1084/jem.186.7.999 ◽

1997 ◽

Vol 186 (7) ◽

pp. 999-1014 ◽

Cited By ~ 128

Author(s):

Hideaki Ishikawa ◽

Daniel Carrasco ◽

Estefania Claudio ◽

Rolf-Peter Ryseck ◽

Rodrigo Bravo

Keyword(s):

T Cells ◽

Lymphocyte Proliferation ◽

Cytokine Production ◽

Cell Types ◽

Homozygous Deletion ◽

Binding Activity ◽

Activated T Cells ◽

Physiological Relevance

The nfkb2 gene encodes the p100 precursor which produces the p52 protein after proteolytic cleavage of its COOH-terminal domain. Although the p52 product can act as an alternative subunit of NF-κB, the p100 precursor is believed to function as an inhibitor of Rel/NF-κB activity by cytoplasmic retention of Rel/NF-κB complexes, like other members of the IκB family. However, the physiological relevance of the p100 precursor as an IκB molecule has not been understood. To assess the role of the precursor in vivo, we generated, by gene targeting, mice lacking p100 but still containing a functional p52 protein. Mice with a homozygous deletion of the COOH-terminal ankyrin repeats of NF-κB2 (p100−/−) had marked gastric hyperplasia, resulting in early postnatal death. p100−/− animals also presented histopathological alterations of hematopoietic tissues, enlarged lymph nodes, increased lymphocyte proliferation in response to several stimuli, and enhanced cytokine production in activated T cells. Dramatic induction of nuclear κB–binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes. Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-κB complexes in various cell types and its absence cannot be efficiently compensated for by other IκB proteins.

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